Protective Immunity Against HIV1

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Protective Immunity Against HIV-1

• Rupert Kaul
• University of Toronto, Canada

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HIV immunity - overview

• Review of HIV-1, life cycle, transmission
• Humoral immunity
• In infected individuals - neutralization, escape,
  debris
• As an vaccine strategy - active, passive
• Cellular immunity
• In infected individuals - control, escape,
  evolution
• As a vaccine strategy - active (passive ?) - SIV,
  HIV
• Innate immunity
• Soluble factors - Trappin, SLPI, etc
• Cellular factors -TRIM5a, APOBEC, etc

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HIV protective immunity

• Various possible meanings
• Sterile immunity no infection after contact
• Controlling immunity infected, but do not
  develop immunosuppression
• Transmission immunity infected, but dont shed
  or transmit virus (related to 2)

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Two contrasting facts

• (1) HIV has spread widely and rapidly (and
  increasingly in women)

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• (2) and yet HIV is relatively difficult to
  transmit

UK PEP Guidelines, 2006.
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HIV transmission viral mathematics
GENITAL INFECTIONS
Quinn T, NEJM, 2000 Sheth P, J Immunol, 2005
Kovacs C, Lancet 2001 Pilcher C, JID, 2004.
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HIV structure
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HIV - virus, genetics

• HIV is a lentivirus - an RNA virus from the class
  of retroviruses
• 2 HIV species (1 and 2) - 40-50 homologous
• Several HIV clades - A,B,C,D,A/E,O (others) -
  70-80 homologous
• Within a clade - 85-90 homologous
• Within an individual - quasispecies gt95
  homologous
• About 109 viruses produced per day, error-prone
  reverse transcriptase (q 10-4-10-5)

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HIV-1 life cycle
(1) HIV-1 attachment (2) Fusion (3) Cell entry
(4) Reverse transcription, formation of the
pre-integration complex (PIC) (5) Nuclear
transport (6) Chromosomal integration of DNA
provirus (7) Transcription of viral RNA (8)
Nuclear export of RNA (9) Translation and
processing (10) Membrane transport (11) Virion
assembly (12) Budding (13) Maturation.
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HIV - clinical progression
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Profound gut (GALT) CD4 depletion may drive HIV
pathogenesis
Mehandru et al. J Exp Med, 2004.
Brenchley et al. J Exp Med, 2004.
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?4?7 and HIV infection
Sattentau Q. Nat Immunol, 2008.
Mora J. Nature, 2003.
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perhaps via systemic lipopolysaccharide
Brenchley et al. Nat Med, 2006.
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Humoral immunitypros and cons as basis for
an HIV vaccine
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HIV antibody responses (1)

• IgG response is ubiquitous - basis of diagnosis
• Most people do make neutralizing Abs against
  their own virus
• BUT only work against the virus that was there a
  few months ago - not the one that is there today
• Failure of infused cocktail to impact infection
  for more than a few days

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HIV antibody responses CONS

• Conformational masking
• Lack of broad neutralization
• Shielding of highly-conserved coreceptor binding
  regions by hypervariable loops
• Irrelevant" antibodies vs gp120 monomers, or
  non-critical regions of the gp120-trimer (debris)
• Surface glycosylation focused changes in glycan
  packing prevent neutralizing Ab binding but not
  receptor binding

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Kwong P. Nature, 2002.
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Wei X. Nature, 2003.
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HIV antibody responses PROS

• BUT some are specific for conserved regions, do
  neutralize primary virus, synergize - how can we
  focus humoral responses?
• F105, b12 - CD4 binding site of gp120
• 2G12 - complex gp120 epitope
• 2F5, 4E10, Z13 - gp41
• Passive infusion of cocktail ONLY model of
  sterilizing immunity (MCH, PEP trials)
• ?Pre-formed Ab applicable via microbicides

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Passive immunizationONLY model of sterile
protection
Nishimura Y et al. PNAS, 2003.
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• Viruses early in infection are less glycosylated,
  more easily neutralized (Overbaugh J, 2005).
• Borne out in some studies, not others

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(2) Cellular immunity
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HIV and cellular responses PROS

• In primate models, vaccine-induced CTL can slow
  progression, improve viral control
• CTL are associated with control after acute HIV
  infection
• CTL (CD8) impose major immune pressure on virus
  (SIV, HIV)
• HIV-specific CD4, CD8 responses found in
  exposed, uninfected populations

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Immune time course post infection
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CD8 depletion and plasma SIV load
Jin X et al. J Exp Med, 1999
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Kiepela et al. Nature, 2004
Musey et al. NEJM, 1995
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Kiepela et al. Nature Medicine, 2007
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Barouch et al. Science, 2000.
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CONS HIV evasion of cellular immunity

• Proviral latency - no antigen expressed
• Downregulation of HLA class I (nef, vpu)
• Upregulation of Fas ligand - back-killing via
  apoptosis
• Mutation
• epitope mutation prevents HLA binding, TLR
  binding
• flanking mutations prevent processing
• Loss of HIV-specific T help /- persistent
  antigen - impaired CD8 function

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Escape from CTL control
Mutation
Other
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CD8 escape variants are transmissible
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Impaired CTL maturation?
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Viral persistence may necessitate dysfunction
Wherry, J Virol. 2003.
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Ahmed R, et al. J Exp Med, 2006.
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HIV superinfection can occur

• Despite strong CTL, patients can be infected by a
  second strain of HIV-1

• But may be less common than initial infection
• ?? Half as likely to happen (very unclear)

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Real life HIV protection? exposed uninfected
individuals

• People who should be infected but arent
• sex workers, discordant couples, etc
• Several correlates
• Lack of CCR5
• HIV specific cellular immunity lysis, IFNg,
  proliferation (generally low level)
• HIV neutralizing IgA
• ? Actually mediating protection vs.
  paraphenomenon - impossible to prove in an
  observational study
• ALSO studies often poor - small, unblinded, etc

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Immune correlates of HIV protection high risk
Kenyan sex workers

• Prospective, nested case control study
• ? Baseline immune correlates of HIV
  non-acquisition

Hirbod et al. AIDS, 2008.
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IgA and proliferation were ?additive
Hirbod et al. AIDS, 2008.
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Immune correlates of HIV protection long-term
nonprogressors

• People who should be sick but arent
• Infected for gt10 years, normal immune system, low
  VL
• Also elite controllers - low/undetectable VL
• Several correlates
• Certain class I HLA types B5701/03, B27, etc
• HIV specific cellular immunity breadth?
  Function?
• No good humoral associations
• ? CTL mediating protection vs. paraphenomenon -
  again, impossible to prove in an observational
  study

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Polyfunctionality and survival

• Progressors
• LTNP

Betts, M Blood, 2006
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Vaccine-induced CTL are they useful?

• Macaque models - several show that inducing
  SIV/SHIV-specific CD8 T cells can lower viral
  load, slow/prevent progression
• Generally dont prevent infection - but maybe
  could protect against real challenge?
• Hard to induce using candidate vaccines
• Case of human infection post vaccine despite
  strong CD8 responses against dominant epitope

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STEP TRIAL

• Merck HIV vaccine
• Adenovirus (Ad5) based, sole goal was to induce
  cellular immunity
• Did so fairly well, BUT
• No protection against infection
• No impact on post-infection VL
• Increased HIV rates if prior adeno infection

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Innate immunity, mucosal immunity, etc
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Genital/mucosal protective factors

• Genital tract repels gt99 of HIV exposures
• Combination of factors
• Intact epithelium
• Mucus, pH, SLPI, lactoferrin, Trappin-2, etc
• ?Adaptive mucosal immunity
• Lack of co-infections also important

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What are the major genital HIV targets?
Hladik F. Immunity, 2007.
Haase A. Nat Imm Rev, 2005.
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Penile HIV target cells
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Mucosal immune protection vs HIV

• 3 large RCTs in SSA now show clear benefit
• Very consistent results in Uganda, Kenya, SA
• Efficacy ITT 55, OTA 63
• In Kenya incidence 2.1 vs 4.2
• No short term behavioural disinhibition
• is being followed prospectively

Viewpoint. Coates T, et al. Lancet, 2007.
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Generating mucosal immunity
Holmgren. Nat Med, 2005.
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There is more to a mucosa than just immune
responses
Freeman E, AIDS, 2006
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Cervical target cells in HIV(-) women

• These associations were seen in HSV-2 infected
  women in the absence of HSV-2 DNA shedding or
  clinically apparent ulceration

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and genital/blood HIV levels
Nagot et al. NEJM, 2007.
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Other innate protection

• Innate mucosal proteins
• Trappin-2 increased in resistant FGT
• APOBEC3G
• Host cytidine deaminase
• Deaminates dC?dU on ss-cDNA, then get G?A on next
  strand, mutational death
• Vif targets APOBEC for proteosomal degradation
• TRIM5a
• Species-specific protection against retroviruses
• Sooty mangabey model
• Infected by SIVSM (HIV2) - high VL, high CD4
• ? via lack of immune activation, low CTL, high
  Tregs

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TRIM-5 alpha mechanism
Emerson M. PNAS, 2006.
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Summary

• No good model of active immunity to HIV
• Cellular responses are primarily responsible for
  (inadequate) control post-infection
• Antibody responses against specific epitopes may
  provide passive protection
• Innate important in transmission possible
  innate vaccine or microbicide?
• Treatment of co-infections, circumcision may be
  effective mucosal immune therapies